12alpha-halo-delta20(22)-furostene-3beta, 26-diol-11-one 3, 26-diacylate and preparation thereof



sited States Patent This application-is a division of our application Serial No. 576,259, filed April 5, 1956, now US. Patent No. 2,963,495, which in turn is a continuation-in-part of our parent application 'SerialNo. 519,682, filed Iulyl, 1955.

This invention relates to the'synthesis of valuable steroids; and it has for its object the provision of (I) an advantageous process of preparingsteroids of the pregnane (including the :allopregnane, pregnen-e and pregnadione) series having a IZOt-hBlOgGIL substituent and an '11- keto or llfi-hydroxy substituent, and of (11) certain steroids useful themselves as physiologically active steroids or as intermediates inthe preparation of said physiologically active steroids.

The process of this invention essentiallycornprisesi (a) converting a 3fl-acyloxy-llfl,l2,B-epoxy-5ix,2;2 (either 'a or b)-spirostane' to the corresponding '12u halo 1lB-hydroxy derivative; (12) oxidizing said derivative'to the 120: halo-ll-keto derivative; (0) opening-the F-ring to produce a 12ot halo-A -furostene-1l-0ne-3/3,2:6-diol 3,26-

diacylate; (d) opening the E ring to produce a l-2a-halo- J esters thereof with hydrocarbon carboxylic acids having methyl-S-acyloxy)pentanoate; (e) converting said allopregnane to a l2ot-halo-allo-pregtnanel60,l7a-oxido-l1,

ZO-diOne-Sfi-ol 3-acylate eitherdirectly o-r through' the 12a-halo-A -allopregnene-I 1,2O-dione-3fl-ol 3-acylate do rrva-tive; (f) converting said epoxide to a 12a-halo:-l6fl-' i iodo (or bromo)-allopregnane-11,20-dione-3,B,l7u-diol 3- acylate derivative; and (g) dehalogenating the latter to the corresponding l2a-halo-allopregnane-1l,20-dione-3/3, l7oz-di0l 3-acylate derivative. 5

The resultant l2a-halo-allopregnane-l1,20-dione-3B,

17a-diol 3-acylate can then be saponified to the correy sponding" l2a-halo-allopregnane-1 l,20-dione-3,8,'l7u-dio1 which in turn can'either be converted to the correspondmg 12ot-halo-3 ,ZO-diketo- 17 a-hydroxy- 1 1 B-hydroxy (or 11-keto)-steroids of the pregnene series (for example: 12a-halo-A -pregnene-17a-ol-3,ll,2O-trione; 12a-halo-A ene-l7ot-ol-3,11,20-trione; and 12u-halo-A -pregnadiene- 11fi,l7ot-diOl-3,20-di0n6) or to the corresponding 12a,- halo-3,ZO-diketo-17a,21-dihydroxy-1lfi-hydroxy (or 11- keto)-steroids of the pregnene series or 21-esters thereof [e.g., 12a-halo-A -pregnene-l7a,2l-diol-3,11,20-trione and esters thereof (particularly esters With hydrocarbon carboxylic acids of less than ten carbon atoms as exemplified by acetic and benzoic acid esters), l2a-halo-A -pregnene- 11B,l7a,2l-triol-3,20-dione and 21-esters thereof, 12ozhalo-A -pregnadiene-17a,21-diol-3,11,20-trione and esters thereof, and l2cx-halo-A -pregnadiene-ll5,17ut,21-triol-3, 20-dione and esters thereof]. This series of conversions is effected by oxidizing the l2a-halo-allopregnane-11,20 (llOI13,B,17 a-dl0l [after treatment Withbrornine to form the corresponding 12a-halo-21-bromo-allop-regnane-11, 20-dione-3B,l7a-diol derivative and converting the latter with an alkali salt of an organic acid to the corresponding l2ot-halo-allopregnane-11,20-dione-3B,17a,2l-triol 2l-acylate derivative if a 21-hydroxy steroid is desired] to the corresponding l2a-ha1o-allopregnane-3J1,20-trione-17u- 01, and thence to a 2a,4u-dibromo-12a-halo-allopregnanel7a-ol-3,ll,20-trione by treatment with bromine. The

dibromide can then either be converted directly to a mhalo-A i-pregnadiene-17a-ol-3,l1,20-trione by means of a tertiary base (e.g.,' collidine) or to a 12a-halo-A -pregnene-17a-ol-3,l1,20-trione via the 2u-iodo-l2u-halo-A pregnene-17a-ol-3,l1,20-trione intermediate. To convert the resultant ll-keto steroid'to the corresponding 11phydroxy derivative, two difi'erent series of reactions are possible. First, the 12a-halo-3,l1,20-triketo-17a-hydroxy steroid can be reacted with a semicarbazide to give the 11-keto-3,ZO-disemicarbazone, thence to the l1,B-hydroxy- 3,20-disemicar-bazone by means of an alkali metal boron tetrahydride and finally to the 1lfi-hydroxy-BJO-diketone by reaction with nitrous acid; or second, the 12a-halo-3, 11,20-t1ik6i0-17ct-hYdIOXY steroid can be converted to the 3,20-diketal-11-ketone derivative, treated with alkali metal boron tetrahydride to form the 3,20-diketal-1lfihydroxy derivative and then hydrolyzed'toyie'ld thell hydroxy-3,20-diketone.

The 3,20-diketal-l lli-hydroxy serves the additionalfuncediate for the preparation-of r1211?- halo-llfi-hydroxy (or ll-keto) derivatives generally; since tion of being an inte this intermediate upon reaction with a base yields the 11,8l2fl-epoxide-3,20-diketal which can be hydrolyzed by means of a dilute acid to the 11fl,12;3-epoxide-3,20-d1ketone, which in turn can be treated in the usual manner with a 'hydrohalic-acid to :form the 12uc-h3l0-l1/3-hYdIOXY derivative (Whichican, if des halo-l l-keto derivative) The compounds of this-inventioncomprise: (A) 12afiuoro-5u-spirostane-3fl3li-diol 3-acylate (preferably the edjbe oxidized to the less than ten carbon atoms as exemplified by the acetate and benzoate); (B) IZa-halb (preferably chloro or fluoro)-5a-spirostane-3fi-ol-il-one 3-acylate; (C) 1211- halo (preferably chloro or fluoro)-A -furostene 3,8,26-diol-11-one 3,26-diacylate; (D) l2u-halo prefer- 12a-halo (preferablychloro or fluoro)-A -allopregnane- 3fl-ol-1-1,20-di0ne 3-acylate; (F) 12a-halo (preferably chloro or fluoro)-allopregnane-16a,17a-oxido-3fi-ol-l-1, ZO-dione 3-acylate; (G) 1206-11310 (preferably chloro or iluoro)-l6,B-bromo (or iodo)-allopregnane-3fi,17u-diol- 11,2( )-dione 3-acylate; (H)12 a-'halo steroids of the generalformula CHzY | o=z '----on I v "wherein the 1,2 and 4,5' positions are either saturated or double-bonded, R is hydrogen, R ishydroxy or acyloxy (preferably an ester of a hydrocarboncarboxylic acid having'less than ten carbon atoms),"'or together R and R is keto, ketal (preferably either a ketal of'a lower alkanol or a lower alkariediol), or semicarbazone lit hydroxy or acyloxy (preferably an ester of a hydrocarbon carboxylic acid having less than ten carbon Patented Oct. 24, 1961 atoms), and Z isketo, ketal (preferably either a ketal 11/3,12,8-epoxy steroids of the general formula of a lower alkanol or a lower alkanecliol) or semicarbazone; (I) 20:,4oc-Clibl'0II1O-d2ot-h3l0 steroids of the gen- F eral formula :2

5 0 -01; $HzY' W I X 0=o i----OH g I wherein the 1,2 and 4,5-positions are either saturated or double-bonded (preferably the 1,2-position is saturated O: r and the 4,'5-position is double-bonded), and Z is keto or I ketal (preferably either a ketal of a lower alkanol or a lower alkanediol) [it being understood that if R and R is ketal, the double bond, if any, in the 4,5-position shifts to the 5,*6-position], and Y is as hereinbefore defined. The final products of this invention [Compounds H, wherein the 4,5-position is double-bonded and Z and R+R' are keto] are physiologically active steroids which possess glucocor-ticoid as Well as mineralocorticoid activity. Thus, these new steroids of this invention can be administered instead of, and in the same manner as,

cortisone or hydrocortisone in the treatment of rheumatoid arthritis and dermatomyositis, or in the same 1 manner as d'esoxyoorticosterone in the treatment of Addi- 8 1 sons disease or adrenal insufliciencies. The dosage for wherein X :is a-halo (preferably chloro or fluoro) and Y is hydrogen, hydroxy or acyloxy (preferably an ester of a hydrocarbon carboxylic acid having less than ten carbon atoms); (J 2a-iodo-12a-halo steroids of the general formula CHzY v I such administration is, of course, dependent on the rela- O: tive activity of the compound. The IZa-bI'OIIlO-ll-kCtO- 1 steroids are of further use as intermediates in the preparation of the corresponding 12-debromo derivatives, to p which they are converted by treatment with either'zinc dust in acetic acid or chromous chloride.

0: For a clearer understanding of the foregoing general Br and following detailed description of the processes of this invention, reference is made to the following schematic analysis, wherein the capital letters designate the general class of compounds and the Roman numerals the wherein X and Y are as hereinbefore defined; and (K) specific embodiments thereof of the examples:

NaOH I g 1 Compounds H containing oxo radicals in the 3- and I l-positions can then be converted to the corresponding Br-- NaI xrgm o XXXV CHgY' -1=1 8-hydroxy derivatives or (to an -11-keto or 11,8-hydroxy derivative having a different halogen substituent in the l2a-positionby the following series of steps:

XLIV X=Ol; Y=OH (1,2-saturated; 4,5- double bonded) O L5H H L0H HO ---OH QQ IQ at I 5 Z 5 11 HI: H XLV X=Cl; Y=OH; XLVI X=Cl; Y=OH; XLIX X=C1; Y=OH Z=OCHzCHzO Z=OCH2CHzO- (1,2-saturated; 4,5 (1,2-saturated; 5,6- (1,2-saturated; 6,6- double-bonded) double-bonded) double-bonded) L X=Br; Y: 0 H 0 O (1,2-saturated; 4,5- double-bonded) CHiY OH Y as o 5 l Ka Kb XLVII Y=O H (1,2-saturated; 4,5- double-bonded) XLVIII Y=OH3C 0 0 (1,2-saturated; 4,5- double-bonded) pound III, and 12u-fluoro-5a,22a-spirostane-3fl-ol-11- T0 prepare the steroids of this invention, 3fi-acyloxyone 3-acetate. Compound IV]. This reaction is pref- 11B,12,6-epoxy-5u-spirostane (e.g., 3Baceto-xy-11 8,12perably conducted in an inert organic solvent (e.g., epoxy-5a,22a-spirostane) is treated with a hydrohaiic acid acetone). (preferably either hydrochloric or hydrofluoric acid) in Compounds B are then heated under substantially anthe usual mannuer to yield the corresponding 12a-halo hydrous conditions, preferably in an organic solvent com- (preferably chloro or fiuoro)-1lfl-hydroxy-3fi-acyloxy-5aprising an acid anhydride and a Lewis acid, e.g., pyridine spirostane, Compounds A [e.g., 12a-chloro-5a,22a-spirohydrochloride, to open the F ring, thereby yielding the stane-3/3,11,B-diol 3-acetate, Compound II, and IZa-fiLlOIO- corresponding 12a-halo-l1-keto-3 3-acyloxy-A furo- 5u,22a-spirostane-3fi,llfi-diol S-acetate, Compound I]. stene-26-ol 26-acylate derivative, Compound C, wherein The esterifying radical in the 3-position will depend, of the 26-acyl radical corresponds to the acyl radical of the course, on the particular ester derivative of the epoxyacid anhydride employed in the reaction. Examples of spirostane initially chosen, and since the sole function of such furostene derivatives include 12oc-Ch1OIO-A -fllr0 this ester group is to protect the 3 3-hydroxy1 radical, any stone-3,3,26-diol-11-one 3,26-diacetate, Compound V, and acid is utilizable. Because of their availability, however, l2a-fiuoro-A -furostene-3fl,26-di 1- 3,25 diamthe preferred acids are those of hydrocarbon carboxylic 5 tate, Compound VI. The reaction is preferably eflected acids containing less than ten carbon atoms and include by refluxing the spirostane and pyridine hydrochloride in the lower alkanoic acids (e.g., acetic, propionic, and enacetic anhydride under anhydrous conditions. anthic acids), the aromatic acids (e.g., benzoic, toluic and Compounds C are then oxidized either by means of a xyloic acids), the cycloalkanoic acids (e.g., cyclohexaneperacid (e.g., peracetic acid formed in situ by means of carboxylic acid), and the aralkanoic acids (e.g., phenylacetic acid and hydrogen peroxide) or chromic acid to acetic and phenylpropionic acid). yield the corresponding IZa-halo-l1-keto-3fi-acyloxy-allo- Compounds A are then oxidized, as by treatment with pregnane-16fi-ol-20-one 16-(4-methyl-5-acyloxy)pentanochromic oxide, to the corresponding 12a-ha1o-l1-'keto-3fl ate, Compounds D [e.g., 12a-chloro-allopregnane-3B,16B- acyloxy-5a-spirostane derivative, Compounds B [e.g., 12adiol-11,20-dione 3-acetate, 16-(4-methyl-5-acetoxy)pentachloro-5a,22a-spirostane-3;8-o1-11-one 3-acetate, Comnoate, Compound VII, and 12or-fluoro-allopregnane-3fi,

9 16,8-diol-ll,20-dione B-acetate, l6-(4-methyl-5-acetoxy) pentanoate, Compound VIII].

Compounds D can then either be dehydrated by treatment with a base (e.g., potassium hydroxide) to the corresponding llu-halodl-keto-3p-acyloxy-A -allopregnene- ZO-one, Compounds E (e.g., l2a-chloro-A -allopregnene- 3fl-ol-ll,20-dione 3-acet-ate, Compound IX, or IZu-IIUOI'O- A -allopregnene-3B-ol-l1,20-dione 3-acetate, Compound X), and thence by treatment of the resultant Compounds E with hydrogen peroxide and an alkalihydroxide or carbonate to the corresponding IZa-halo-ll-neto-3B-acyloxyallopregnane-16w17ot-oxido-20-one, Compounds F (e.g., l2oz-chloro-allopregnane-l6u,l7a-oxido-3fi-ol 11,20 dion'e'3-acetate, Compound X1, or 12a-fiuoro-allopregnanel6u,17a.-oxido-3p-ol-11,20-dione 3-acetate, Compound XII) or directly to Compounds F by treatmentof Compounds D With hydrogen peroxide in a basic medium (e.g., methanolic sodium hydroxide).

Compounds F are then hydrohalogenated by treatment with either hydrobrornic or hydroiodic acid to yield the corresponding 12a-halo-l6fi-bromo (or iodo)-l1-l:eto-3flacyloxy-allepregnane-lh ol 20 one derivatives, Compounds G (e.g., l2a-chloro-l6,6-brorno-allopregnane-3B, 17a-diol-l1,20-dione 3-acetate, Compound XIII, 12achloro-16fi-iodo-allopregnane-3fi,17ot-diol-l 1,20 dione 3- acetate, Compound XIV, and IZu-fiUOI'O-l6fi-lOdO-8ll0- pregnane-3,B,l7a-diol-l1,20-dione 3-acetate, Compound XV).

Compounds G are then dehalogenated in the 16position by treatment with a reducing agent such as Raney nickel or palladium and hydrogen to yield the corresponding l2a-halo-11-keto-35-acyloxy-allopregnane-l7a-ol 20- one derivatives, Compounds Ha (e.g., l20cCl1l01'0-allO pregnane-3fi,17a-diol-l1,20-dione 3-acetate, Compound XVI, and 1Ze-fiuor0-all0pregnahe-3{3,17a-diol-1l,20-dione, Compound XVII).

Compounds Ha can then be saponified by treatment with an acid (e.g., perchloric acid) or base (e.g., potassium carbonate) in a lower alcohol to yield the corresponding lZu-halQ-aIIopregnane-ESB,l7u-di-ol-l1,20 dione, Compounds Hb (e.g., 12or-cl1loro-allopregnane-3,6,17mdiol-ll,20-dione, Compound XVIII, and l2a-fiu oroallo pregnane-lBJM-diol-l1,20-dione, Compound XIX).

If a ZI-hydroxy steroid is desired, Compounds Hb are then brominated in the ill-position by treatment with bromine in an inert organic solvent to yield the correspond,

ing 12oc-l'121lO-2l-bIOmO-21ll013l'6gt12lnE-3fi,17ot-diOl-l1,2G-dione, Compounds I-Ic (e.g., lZa-chIoro-Zl-bromo-allopregnane-BflJh-diol-l1,20-dione, Compound XX, and 120L- tluoro-Zl-bromo-allopregnane-3,B,l7ot-diol 11,20 dione, Compound XXI) in which the Zl-bromine atom is then replaced by an acyloxy group by means of an alkali salt of an organic acid, preferably acetic acid, whereby the resultant Zl-Substituent is an ester of the acid employed, to yield the corresponding lZa-halo-Zl-acyloxy-allopregnane-3, 3,l7ot-diol-l1,20-dione, Compounds I-Id (e.g., 12o:- chloro-allopregnane-3 3,17,2l-triol 11,20 dione 21-acetate, Compound XXII, and 12a-fluoro-allopregnanedp2, 17a,2l-triol-ll,20-dione Zl-acetate, Compound XXIII), which may then be hydrolyzed, if desired, to yield the free Zl-hydroxyl derivatives.

Compounds I-Id or Compounds Hb (if a 2l-unsubstituted steroid is desired) are then oxidized by treatment with chromic acid to yield the corresponding -12a-halo- 3,11-diketo-allopreguane, Compounds He (e.g. 12a-chloro allopregnane 17a,21-diol-3,l1,20-trione ZI-acetate, Compound XXIV, l2ot-fluoro-allopregnane-17a, 2l-diol- 3,11,20-trione 21-acetate, Compound XXV, IZa-ChlOIO- allopregnane-lh-ol-SJ1,20-trione, Compound XXVI, and 12u-fluoro-allopregnane-17u-ol-3,11,20-trione, Compound XXVII) To introduce a double-bond in the 4,5-position, Compounds He are treated with at least two moles of bromine per mole of steroid, whereby IZa-halo-ZaAu-dibmmo-allopregnane derivatives, Compounds I are formed (e.g., 12cc chloro-2a,4u-dibromo-allopregnane-170:,21- diol-3,11,20-trione ZI-acetate, Compound XXVIII, 12afluoro 204,40; dibromo-allopregnane-17a,21-dio1-3,11,20- trione 21-acetate, Compound XXIX, t-ChIOIO20t,4OL- dibromo allopregnane-1 7a-ol-3,l1,20-trione, Compound XXX, and 12a-fluoro-2ot,4u-dibromo-allopregnane-17aol-3,ll,20-trione, Compound XXXI).

To prepare the corresponding M-pregnene, Compounds I are heated wtih an iodide salt (e.g., sodium iodide) whereby the corresponding 12ot-halo-2a-iodo-M-pregnene derivative, Compounds J, are formed (e.g., IZOt-OIIIOI'O- 2u-iodo-co-rtisone 21-acetate, Compound XXXII, 12afluoro-2a-iodo-cortisone 21-acetate, Compound XXXIII, 12a chloro Za-iodo-l1--keto-17ahydroxyprogesterone, Compound XXXIV, and l2a-fluoro-2a-iodo-11-keto-17ahydroxyprogesterone, Compound XXXV), andthe iodo radical is removed by reaction with a reducing agent such as aqueous chromous chloride to yield Compounds Hf (e.g., 12a-chloro-cortisone, ZI-acetate, Compound XXXVI, 12a-fluoro-cortisone ZI-acetate, Compound XXXVII, 12a-chloro-1l-keto-l7ot-hydroxyprogesterone, Compound XXXVIII, and 12a-fluoro-11-keto-l7a-hydroxyprogesterone, Compound XXXIX).

To obtain a A -pregnadiene derivative, Compounds I are heated with collidine to yield the corresponding A -pregnadiene derivative, Compounds Hg (e.g., 12achloro A pregnadiene-17,2l-di0l-3,11,20-trione 21- acetate, Compound XL, 12a-fluordA -pregnadiene-l7d, 2l-diol-3,11,20-trione 21-actate, Compound XLI, 12achloro A pregnadiene-17u-ol-3,11,20-trione, Compound XLII, and lZu-fiuoro-A -pregnadiene-17a-ol-3,11, 20-trione, Compound XLIII).

Compounds Hf and Hg, containing a 2l-acyloxy radical can behydrolyzed in the usual manner, as by the use of a salt of a strong base and a weak acid (e.g., potassium carbonate) to yield the free 2l-hydroxylderivative (e.g., 12a-chlorocortisone, IZa-flHOI'OCOIfiSOHe, 12m chloro-A -pregnadiene-17,21-di0l-3,11,20-trione and 120: fluoro A -pregnadiene-17a,21-diol-3,11,20- trione);

Compounds He, H and Hg can further be converted to the corresponding 1l 8-hydroxy derivatives by either of two processes. In the first process, the steroid is treated with semicarbazide in a lower alcohol to yield the 3,20-disemicarbazone, Compounds Hi1, which are then treated with an alkali metal boron or lithium tetrahydride (e.g., potassium boron tetrahydride) in an organic solvent inert towards the tetrahydride (either in the presence or absence of water) to yield the corresponding llfl-hydroxy derivative, Compounds Hi, and the resultant steroids are then reacted with nitrous acid in a dilute mineral acid (e.g.,hydrochloric acid) to yield Compounds H, having an llfi-hydroxy radical, the 12mhalo radical of the starting steroid and keto groups in the 3,20-positions (e.g., l2a-chlorohydrocortisone, 12ocfluorohydrocortisone, 12oz chloro 11B,17a-dihydroxy-= progesterone, lzu-fluoro-l 1p,17a-dihydroxy-progesterone,

12 ohloro-A -pregnadiene-1118,l7a,21-triol-3,20-dione,

12cc fiuoro-n -pregnadiene-l 1B,17a,21-lIiOl-3,20-dl0116, 12oz chloro A pregnadiene-l1B,17a-diol-3,20-dione, 12a-fluoro-A *-pregnadiene-1 1,8,].70t-dlOI-3,20-CIIOI16, 120tchloro allopregnane 11B,l7a,21-triol-3,20-dione, 12afluoro allopregnane 11,8,17et,21-triol-3,20-dione, 120cchloro allopregnane-l1p,17or-diol-3,20-dione and 12afluoro-allopregnane-l 1B,17oc-Cli0l3,20-di0116) In the second process, Compounds Hf or Hg are first hydrolyzed and then ketalized by treatment with a l,2-

glycol (e.g., ethylene glycol) in an inert solvent in the presence of an acid catalyst, to form the corresponding 3,20-diketal derivatives, Compounds Hj, which are then reduced with an alkali metal boron or lithium tetrahydride, as described hereinbefore, to yield the llfi-hydroxy 3,20-diketal derivative, Compounds Hk. The latter are then either treated with a dilute acid, such as sulfuric acid in methanol, to yield a 12a-halo-11p-hydroxy-3,20-

diketo steroid wherein the halo group is that of the starting steroid, or dehydrochlorinated (when the l2uc-113l0 substituent is chlorine) to the corresponding 11,13,125- epoxide, Compounds Ka, by treatment with a salt of a strong base and a weak acid (e.g., potassium carbonate). The resultant epoxide ketalized in the 3,20-positions, is then hydrolyzed with dilute acid (e.g., sulfuric acid) to yield the corresponding 11fi,12/3-epoxy-3,20-diketo derivative, Compounds Kb, which can then be treated with a hydrohalic acid (e.g., hydrofluoric, hydrochloric, hydrobromic, or hydroiodic acid), preferably after esterifying any free 21-hydroxyl radical present, to yield the respective 12oc-l1Ell0-11/3-hYdIOXY derivative. The resultant 12ozhalo-ll/S-hydroxy steroid, can, if desired, be oxidized with chromic acid to its 12u-halo-11-keto derivative, thereby affording a generalized method for producing any 12u-halo-l1-keto derivative.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 12a. fluoro 5a,22a spirostane 35,115 diol 3 acetate (1) and 9a fluoro 5a,22a spirostane 35,125 diol S-acetate Into a solution of 2 g. of llfl,l2p-epoxy-5a,22aspirostane-3fi-ol 3-acetate in 76 ml. of chloroform and 4 ml. of absolute alcohol is passed with stirring at a stream of hydrogen fluoride. After 10 minutes two layers form and the addition of hydrogen fluoride is terminated. After 75 minutes at 0, the reaction mixture is neutralized with a suspension of sodium bicarbonate in Water and the layers separated. The chloroform is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue upon one crystallization from chloroform-alcohol furnishes pure 9ot-fluoro-5a,22a-spirostane3fl,12,6- diol 3-acetate having the following properties: M.P. about 25l252; 70 (c. 0.96 in chloroform).

ANuiol max.

max.

Analysis.Calcd. for C H O F (534.66): C, 69.64; H, 8.86. Found: C, 69.76; H, 8.61.

The mother liquors of the above reaction with hydrogen fluoride are combined and dissolved in 10 ml. of benzene and 20 ml. of hexane. After centrifuging off a small flocculent precipitate, the resulting solution is c-hromatographed on 15 g. of sulfuric acid-Washed alumina. Elution of the column with 700 ml. of a mixture of one part of benzene and two parts of hexane furnishes after recrystallization from 95% ethanol, pure 12oc-fi1l0- ro-m,22aspirostane-3fi,1lfi-diol 3-acetate having the following properties: M.P. about 239-241"; [06113 44 (0. 0.65 in chloroform);

12 EXAMPLE 2 12oz chloro 5a,22a spirostwne 3t? ol l1 one 3- acetate (III) A solution of 3.43 g. of BB-acetoxy-l2a-chloro-5ot,22aspirostan-llB-ol (II) (see I. Schmidlin and A. Wettstein, Helv., 36, 1241 (1953)) in 340 ml. of reagent grade acetone is oxidized dropwise, with stirring at room temperature with 4.1 ml. of 'CrO solution (excess, calc., amount 2.4 ml. solution containing 200 mg. CrO and 320 mg. conc. H in 1 ml. water). The excess CrO is destroyed by addition of 1 ml. of ethanol and after addition of 100 ml. of water, the solution is decanted from remaining salts, concentrated in vacuo until most of the acetone is removed and the resulting crystals filtered off. Yield about 2.87 g. (84%), M.P. about 173- 176. The analytical sample is recrystallized several times from ethanol and has the following properties: M.P. about 183185, [001 -80 (c. 0.44 in chloroform),

max.

5.76 5.78,u (doublet), 5.85

EXAMPLE 3 12a. fluoro 5a,22a spirostane 3B ol 11 one 3- acemte (IV) To a solution of 60 mg. of 12o-fluoro-5a,22-spirostane- 36,115-diol 3-acetate (I) in 6 ml. of reagent grade acetone is added at room temperature 0.08 ml. of a solution of chromic acid (200 mg.) and sulfuric acid (320 mg.) in water (1 ml.). After /2 hour 0.25 ml. of alcohol and 5 minutes later 5 m1. of Water is added and the acetone removed in vacuo. The residue is taken up in chloroform and the resulting CHCl -extract washed with water, dilute bicarbonate and again with water. Removal of the solvent from the sodium sulfate-dried extract furnishes the crude ll-ketone, which after crystallization from alcohol has the following properties: M.P. about 203-204; [c1 6 (c. 1.28 in CHCl 5.79 582 (shoulder) EXAMPLE 4 12a chloro A2002) furosten'e 36,26 diol 11 one 3,26-diacetate (V) A solution of 4.45 g. of the l2a-chloro-11-keto-spirostane (III) prepared in Example 2 and 2 g. of pyridine hydrochloride in 23 m1. of acetic anhydride is refluxed under exclusion of moisture for 5 hours. The mixture is then cooled in an icebath and the acetic anhydride destroyed by careful addition of ice. The mixture is extracted with ethyl acetate, the ethyl acetate extract washed free of acetic acid and pyridine, dried over sodium sulfate and evaporated in vacuo. A yield of about 4.84 g. of the crude furostene diacetate (V) is obtained. Several recrystallizations from ethyl acetate yield the analytical sample, M.P. about HS-119; [001 -|-7 (c. 0.4 in chloroform);

Analysis.-Calcd. for C H O Cl (549.13); C, 67.80; H, 8.26; Cl, 6.46. Found: C, 67.88; H, 8.09; Cl, 6.10.

Similarly, by substituting 12ot-fiuoro-5a,22a-spirostane- 3,8-ol-11-one 3-acetate (IV) for the 12u-chlorospirostane in the procedure of Example 4, 12ot-fiuoro-A -furostone-35,26-diol-l1-one 3,26-diacetate (V1) is produced.

13 EXAMPLE 12oz chloro allopregnane 373,165 diol 11,20-di0ne 3-acetate, 16-(4-methyl-5-acet0xy)pentanoate (VII) is no specific U.V. absorption; X2132 Analysis.-Calcd. for C H O Cl (581.13); C, 63.92; H, 7.81. Found: C, 63.56; H, 7.57.

(b) By oxidation with chromatic acid.-To a solution of 100 mg. of the spirostane diacetate (V) in a mixture of 2 ml. of ethylene dichloride, 2 ml. of glacial acetic acid and 0.4 ml. of water is added with stirring at over a 30-minute period 2 ml. of a solution of chromic acid in acetic acid (25 mg./ml.). The reaction mixture is allowed to warm up to and remain at room temperature for an additional two hours. Excess chromium trioxide is destroyed by the addition of 0.5 ml.-.of alcohol and the reaction mixture concentrated in vacuo. The residue is distributed between chloroform and water and the chloroform solution washed with water, sodium bicarbonate and again with water. Evaporation of the sodin-n1 sulfate-dried extract to dryness furnishes a crystalline residue, which after recrystallization from alcohol affords about 50 mg. of the allopregnane derivative VII, MjP. about 183L190".

Similarly, by substituting 12a-f1uoro-A -furostene- 3,6,26-diol-1l-one 3,26-diacetate (V1) for the Hot-chlorofurostene, 12a fluoro arllopregnane 3B,16;8-diol1l,20- dione 3-acetate, 16 (4 methyl 5 acetoxy)-pentanoate (VIII) is formed.

EXAMPLE 6 3-acctare (IX) To a solution of the allopregnane-derivative (VII) in 4 ml. of tertiary butanol is added a solution of 200 mg. of KOH in 0.3 ml. of Water. The mixture is allowed to remain at room temperature for 1.5 hours and then neutralized with dilute hydrochloric acid. Water is added and the mixture extracted with ether. The ether extract is dried over sodium sulfate and the solvent removed in vacuo. The residue is reacetylated with 1 ml. of pyridine and 1 ml. acetic anhydride for 18 hours and after removal of the reagents in vacuo dissolved in 5 ml. of benzene and 5 ml. of hexane for chromatography on 3 g. of sulfuric-acid washed alumina. Elution of the column with benzene-hexane 1:1 furnishes in the first 200 ml. the desired Al -allopregnene derivative (IX), which after crystallization from ether hexane has the following properties: M.P. about 202-204"; [u] -+3 (c. 0.32 in chloroform) Nuiul max.

hits, 229 m (e=1l,000),

Analysis.-Calcd. for C H O Cl (406.94): C, 67.88; H, 7.68. Found: C, 67.77; H, 7.60.

In the same manner, 'by substituting 12a-fluoro-allopregnane 35,165 diol 11,20 dione 3-acetate, 16-(4- methyl-S-acetoxy) pentanoate (VIII) for the chloro compound in the procedure of Example 6, 12ot fluoro-A allopregnene-3B-ol-1-1,ZO-dione 3-acetate (X) is formed.

- nene-3fl-ol-1L20-dione 3-acetate 14 EXAMPLE 7 1200 chloro allopregnane 16a,17ot oxido 3B ol- 11,20-a'i0ne 3-acetate (XI) To a solution of 100* mg. of lZot-chloro-n -allopreg- (IX) in 8 ml. of cold methanol, 0.9 ml. of cold 30% H 0 and 0.37 ml. of 4 N NaOH is added. The mixture is allowed to remain at 0 for 6 hours and then diluted with water and neutralized with dilute hydrochloric acid. Chloroform is added and the resulting chloroform extract is Washed with water, driedover sodium sulfate and evaporated to dryness in vacuo. The resulting residue is acetylated with 1 ml. of acetic anhydride and 1 rnl. of pyridine for 15 hours and after removal of the reagents in vacuo, recrystallized from 95% alcohol. The resulting 16,17-epoxide has the properties described in the following Example 8.

Similarly, by substituting l2ot-fluoro-A -allopregnene- 3/3-ol-11,20-dione 3*acetate (X) for the chloro steroid of Example 7, 12ot-fiuoro-allopregnane-16a,17a-oxido-3B- oll1,20-dione 3-acetate (XII) is formed.

Compounds XI and XII can also be prepared directly from Compounds VII and VIII, respectively, as illustrated by the following example:

EXAMPLE 8 1.93 g. of VII is suspended in 157 ml. of cold methanol and. 17.3 ml. of cold 30% H 0 and 7.8 ml. of cold 4 'N NaOH are added. The mixture is stirred with cooling in an iceoath for 6 hours, then about 50 ml. water is slowly added and the mixture filtered quickly, and washed with dilute acetic acid and water until neutral. The crude epoxide (XI) melts at about 272-275 (yield approximately 847 mg.) The mother liquor is extracted with chloroform, the chloroform extract washed free of hydrogen peroxide and acetic acid with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue after reacetylation with 2 ml. of pyrodine and 2 ml. of acetic anhydride furnishes an additional 330 mg. of XI after crystallization of the crude acety-lation residue from ethanol.

The analytical sample obtained by recrystallization from 95 alcohol has the following properties: M.P. about 278-, --6 (c. 0.21 in chloroform),

Analysis.-Calcd. for C H O 'Cl (422.94); C, 65.31; H, 7.39. Found: C, 65.30; H, 7.44.

EXAMPLE 9 To a solution of mg. of the l6ot,17a-epoxide (XI) in 3 ml. of glacial acetic acid is added 1 ml. of 7% HBr in acetic acid (1 part of 48% aqueous I-IBr plus 6 parts of glacial acetic acid). The reaction mixture is allowed to stand at room temperature over night, poured on ice and extracted with chloroform. The chloroform extract is washed with water, sodium bicarbonate and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue (about 103 mg.) after recrystallization from acetone-hexane furnishes the pure br-omohydrin of the following properties: M.P. about 219-220", 37 (-0. 0.4 in chloroform);

AnaZysis.-Calcd. for C H O C1Br (503.87): c, 54.82; H, 6.40. Found: C, 54.22; H, 6.27.

EXAMPLE 10 blanket 3 ml. of redistilled iodine-free 57% hydriodic acid. The mixture is allowed to stand in the dark for 40 hours, diluted with water and extracted with chloroform. The chloroform extract is washed with water, sodium bicarbonate solution and again with water containing a small amount of sodium sulfite. The chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue (about 547 mg.) crystallizes readily from 96% alcohol and is used in the next step without further purification. An analytical sample after recrystallization from alcohol has the following properties: LIP. about 188-190 (dec.), 14 (c. 0.66 in chloroform);

Analysis-Calcd. for C H O Cl (552.8): C, 49.96; H, 6.19. Found: C, 50.27; H, 6.11.

Similarly, by substituting 12a-fluoro-allopregnane-16a, 17a-oxido-3fi-ol-11,20-dione B-acetate (XII) for the 12mchloro compound of Example 10, 12a-fiuoro-16fi-iodoallopregnane-3fl,17a-diol-11,20-dione Z-acetate (XV) is prepared.

EXAMPLE 11 12a-chloro-allopregnane-3,8,] 7a-di0l-1I ,ZO-dione 3-acetate (XVI) To a solution of 1.0 g. of the 12a-chloro-16fi-iodide (XIV) in 50 ml. of peroxide free dioxane is added 8 ml. of neutral Raney nickel (commercial, pyrophoric) suspended in 10 ml. of dioxane and the resulting suspension shaken in the dark at room temperature for 1 hour. The catalyst is centrifuged 01f and the solution is diluted with water and chloroform. The chloroform-dioxane phase is separated off, dried over sodium sulfate and the solvents evaporated in vacuo. The crystalline residue after recrystallization from 95% alcohol furnishes pure 12achloroallop-regnane-SB,17e-diol-1l,20-dione 3-acetate of the following properties: M.P. about 222224; [a] -35 (c. 0.42 in chloroform);

)\ 2.87 5.79 1, 5.8211 (sh M A solution of 610 mg. of 12a-cl1loroallopregnane-3B, 17a-diol-ll,20-dione 3-acetate (XVI) in 60 ml. of methanol and 0.6 ml. of 70% perchioric acid is refluxed for 2 hours. The solution is then neutralized with sodium bicarbonate solution, diluted with water and the methanol removed in vacuo. Chloroform is added and the resulting extract washed with bicarbonate solution and with water. The dried extract after evaporation of the solvent in vacuo furnishes 12a-chloroal1opregnane-3fi,17a-diol-1 1,20- dione (XVIII), which after recrystallization from 95% alcohol has the following properties: M.P. about 221- 222", 34;

Ami? 29611., 3.95% (shoulder), 5.82M, 592g Analysis.Calcd. for C H O 'Cl (382.92): C, 65.86; H, 8.16. Found: C, 65.99; I-I, 8.26.

Similarly, l2a-fluoro-allopregnane-3fl,17a-diol-11,20-dione S-acetate can be hydrolyzed to the free 3-hydroxyl compound (XIX).

The preparation of the 21-oxy steroids of this invention is illustrated by the following three examples:

16 EXAMPLE 13 IZa-chlorO-ZI-br0m0-all0pregnane-3,B,1 7oc-diOl-11 ,20- dione (XX) To a solution of mg. of 12a-chloroallopregnane- 3B,17a-diol-11,20-dione (XVIII) in 9 ml. of chloroform is added at room temperature with stirring 1.60 ml. of a solution of bromine in chloroform (43.2 mg./ml.). To initiate the reaction a drop of 10% HBr in acetic acid is added. A total reaction time of 8 minutes is required. At the end of that period water is added and the chloroform solution washed neutral with sodium bicarbonate. After drying over sodium sulfate the solvent is removed in vacuo and the .residual bromo compound crystallized from acetone-hexane. Pure 12a-chloro-21-bromoallopregnane-3fi,l7a-diol-l1,20-dione has the following properties: M.P. about l95196 (doc); [0611 37 (c. 0.68 in CHClg);

Analysis.Calcd. for C I-I O ClBr (461.81): 54.61; H, 6.54. Found: C, 55.68; H, 6.72.

Similarly 12a fluoro allopregnane 319,170: di0l 11,20-dior1e can be brominated to 12a-fluoro-21-bromoallopregnane-Bfi,17u-diol-l1,20-dione (XXI).

EXAMPLE 14 12 u-chloro-allopregnane-jfi,1 711,2] -tri0l-1 1 ,20-di0ne 21-acetate (XXII) To a solution of 252 mg. of IZa-ChlOIO-Zl-bI'ODlOHllO- pregnane-3,B,17a-diol-11,20-dione (XX) in 16 ml. of acetone is added in the order given 0.35 ml. of glacial acetic acid, 558 mg. of potassium bicarbonate and 19 mg. of sodium iodide. The resulting mixture is refluxed with stirring for 17 hours, after which period water is added and the acetone removed in vacuo. Ethyl acetate is then added to the aqueous suspension and the layers separated and the ethyl acetate solution Washed with sodium bicarbonate and with water. The sodium sulfate-dried ethyl acetate extract is concentrated to dryness in vacuo and the resulting crystalline residue recrystallized from 95% alcohol. The pure compound has the following properties: M.P. about l58-160; [e5 --17 (c. 0.75 in CHCl mas 5,, 300,1, 5.75 1 (shoulder), 5.82;

EXAMPLE 15 12a-chloro-a.ll0pregnane-1 7 04-21 -dz'ol-3,1 1,22-trione 2] -acetate (XXIV) To a solution of 236 mg. of l2et-chloroallopregnane- 3B,17a,21-triol-11,20-dione 21-acetate (XXII) in 24 ml. of reagent grade acetone is added dropwise with stirring at room temperature 0.67 ml. of a solution of 188 mg. of CrO and mg. of sulfuric acid in 1 ml. of water. After a total reaction time of 25 minutes the excess C10 is reduced with 0.5 ml. of alcohol and water is added. After removal of the acetone in vacuo chloroform is added, the resulting chloroform extract washed with water, sodium bicarbonate solution, and again with water. The solution is then dried over sodium sulfate and concentrated to dryness in vacuo. Pure 12a-chloroallophegnane-l7m,21-diol-3,11,20-trione 21-acetate after recrystallization from acetone-hexane has the following properties: M.P. about 214-216"; [04 +4 (c. 0.83 in CHCl Analysis.-Calcd. for c,,H ,o,c1 (438.92): 0, 62.93; H, 7.11. Found: c, 63.25; H, 7.31.

17 Similarly 12a fluoro allopregnane 3 B,17 x,21 triol- 11,20 -dione 2l-acetate can be oxidized to 12oc-fl1l01'0- allopregnane 17ot,21 diol 3,11,20 trione 21-acetate (XXV).

EXAMPLE 16 l 2a-clzl0ro-allopregnane-1 70t-Ol-3,11 ,ZO-zfrione (XXVI) A solution of 500 mg. of l2a-chloroallopregnane-3B, l7nc-diol-ll,20-dione (XLIII) in 50 ml. of reagent grade acetone is treated dropwise with stirring with 1.4 ml. of a solution of 188 mg. of CrO and 300 mg. of sulfuric acid in 1 ml. of water. After a total reaction time of 40 minutes, 0.5 ml. of alcohol is added and then 20 ml. of water. After removal of the acetone in vacuo the resulting mixture is extracted with chloroform, the chloroform extract washed with water, dilute sodium bicarbonate and again with Water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue upon crystallization from alcohol furnishes pure 12mchloroallopregnane-l7a-ol-3,l 1,20-trine (XXVI) Similarly 12a fluoro -allopregnane 35,170: diol- 11,20-dione (XIX) can be oxidized to IZa-fluoro-allopregnane-17a-ol-3,11,20-trione (XXVH) EXAMPLE 17 12ot-chlore-20:,4ot-dibromo-allopregnane-I 70:,21 -di0l- 3,11,20-tri0ne 21-acetate (XXVIII To a solution of 200 mg. of 12a-chloroallopregnane- 17a,21-diol-3,l1,20-trione 21-acetate (XXIV) in 13 ml. of glacial acetic acid is added at room temperature with stirring 3.35 ml. of a solution of bromine in glacial acetic acid (45.4 mg./ml.). To initiate reaction a few rops of hydrogen bromide in acetic acid areadded. Bromination is complete after 3 hours. The mixture is taken up in chloroform and water and the resulting chloroform extract washed with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue crystallizes readily from acetone-hexane and furnishes the pure dibromide having the following properties; MP. about 179-18l (dec.); [a] +1.5 (c. 1.26 in 'CHCl Similarly 12a-fluono-allopregnane-17a,21-diol-3,11,20- trione 21-acetate (XXV), 120t-Cl'llOI'O-31IOPI6gHE1I16-170tol-3,1l,20-trione (XXVI) and l2ot-fluoro-allopregnane- 17a-ol-3,11,20-trione (XXVII) can be dibrominated t0 the respective 2a,4u-dibromo derivatives (Compounds XXIX, XXX, and XXXI).

EXAMPLE 1s 12a-chlor0-2a-i0d0cortis0ne 21 -acerate (XXXII) A solution of 90 mg of the dibromide (XXVHI) pre pared by the procedure of Example 17 and 24.0 mg. of sodium iodide in 5' ml. of acetone is refluxed for 18.5 hours. The reaction mixture is diluted with water and the acetone removed in vacuo. The resulting suspension is extracted with chloroform and the chlonoform solution Washed-with water containing a trace of sodium sulfite...

Evaporation of the sodium sulfate-dried chloroform extract in vacuo leaves the -2iodide as a crystalline residue, which after recrystallization from acetone-hexane melts at about 166-167 (dec.);

il 240 u 1 8 EXAMPLE 19 21 ot-chlorocortisone 21-acetate (XXXVI) To a solution of 50 mg. of the 12a-chloro-2ot-iodide (XXXI'I) of Example 18 in 3 ml. of acetone is added under nitrogen 0.6 ml. of an aqueous chromous chloride solution (prepared from 5 g. of chromic chloride in 20 ml. of water). The mixture is allowed to remain at room temperature for 10 minutes, after which time water and chloroform are added. The resulting chloroform extract is washed with water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual material crystallizes readily and furnishes pure IZoc-ChIOI'OCOI'tlSOHG acetate upon recrystallization from alcohol, M.P. about Mitt.

(e:14,000). The material obtained in this fashion contains some l2ct-chloroalllopregnane-17a,2l-diol-3,11,20- trione 21-acetate as shown by the lowext-inction coeflicient. It is therefore purified by chromatography on acid-washed alumina (1 g.) in the following manner: the substance is dissolved in 3 ml. of benzene and 3 ml. of hexane, poured on the column and eluted at first with benzene (300 ml.) to remove contaminants. Subsequent elution with benzene containing 5% of chloroform yields pure lZoc-ChlOIOCOItiSOHe acetate of the following properties: M.P. about l96; [u] +82 (c. 1.03 in CHCl kit's... 235 u dd? 5.79% 5.88 6.02% 6.20

Analysis.Calcd. for C I-I O Cl (436.91): .C, 63.22; H, 6.69; Cl, 8.11. Found: C, 63.18; H, 6.84; Cl, 8.06.

Similarly, 12a-fluoro-2a-iodocortisone ZI-acetate, 120cchloro-2a-iod1o-17a-hydroxy-ll-ketoprogesterone and 12dfluoro-2a-iodo-17u-hydroxy1l-ketoprogesterone can be deiodinated to yield l2a-fluorocortisone 2l-acetate (XXV'II) 12a-chloro-17u-hydroxy-1l-ketoprogesterone (XXXVII I) and l2a-fluoro-l7a-hydroxy-ll-ketoprogesterone (XXXIX), respectively.

EXAMPLE 20 IZa-chlorocortisone (XLI V) EXAMPLE 21 V 12ot-chZOrO-A -pregnadiene-I 70.,21 diol 3,11,20 trione 21 -acetate (XL) A solution of 500 mg. of 12OL-ChIOIO-ZOLAOL'dlbI'OmO- allopregnane-17a,21-diol-3,l1,20-trione (XXVIII) in 5 ml. of collidine is refluxed for 45 minutes and the resulting mixture diluted with chloroform and dilute hydrochloric acid. The resulting chloroform extract is extracted with hydrochloric acid until free of collidine and finally with water. The sodium sulfate dried extract is evaporated in vacuo, dissolved in 2 ml. of chloroform and 8 ml. of benzene and the resulting solution chromatographed on 8 grams of sulfuric acid-washed alumina. The column is first eluted with benzene-chloroform 1:1 (400 ml.) to remove impurities, and then with chloroform (400 ml.). The latter solvent elutes the desired 1- dihydro-12a-chlorocortisone acetate (XL), which is obtained in pure form by crystallization from 95% alcohol.

Similarly, 12a-fluoro-2c ,4a-dibromo-allopregnane-17a, 21-diol-3,11,20-trione ZI-acetate (XXIX), l2a-chloro-2a, 4a dibromo-allopregnane-17u-ol-3,11,20 trionc (XXX) and 12a fluoro-2a,4a-dibromo-allopregnane-l7a-ol-3,1l, ZO-trione (XXXI) can be converted to lZu-flHOIO-A pregnadiene-17a,21-diol-3,l1,20-trione 21-acetate (XLI), 12u-chloro-A -pregnadiene-17a-ol-3,1 1,20-trione (XLII) and 12a-fluoro-A -pregnadiene 17cc ol 3,11,20 trione (XLIII), respectively.

Compounds XL and XLI can then be hydrolyzed to the free 21-hydroxy steroid by the method of Example 20.

The following examples illustrate one of the processes for converting the ll-keto steroids to their 11fi-hydroxy derivatives EXAMPLE 22 3,20-diethylene ketal of ZZa-chlorocortisone (XLV) A mixture of 200 mg. of 12a-chlorocortisone (XLIV), 4 ml. of ethylene glycol, 18 ml. of benzene and 15 mg. of p-toluenesulfonic acid monohydrate is refluxed for hours with the aid of a Dean-Stark Water separator. After cooling of the reaction mixture, dilute sodium bicarbonate solution is added and the layers are separated. The aqueous phase is extracted with chloroform, the organic phases combined, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue representing 3,20-diethylene ketal of 12a-chl0rocortisone is used in the subsequent reaction of Example 23 without further purification.

EXAMPLE 23 3,20-diethylene ketal of 12a-chl0r0hydr0c0rtis0ne (XL VI) A solution of 200 mg of the diketal (XLV) prepared in Example 22 and 100 mg. of potassium borohydride in m1. of tetrahydrofuran and 5 ml. of Water is allowed to react at room temperature for 30 minutes and then at reflux for an additional 6 hours. After cooling, the mixture is concentrated in vacuo to remove the bulk of the tetrahydrofuran and the resulting suspension extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and the solvent removed in vacuo. Crystallization of the residue from acetone-hexane yields the 3,20-diketal of 12ccchlorohydrocortisone (XLVI) in pure form.

EXAMPLE 24 IZa-chlorohydrocortisone (XLIX) A solution of 100 mg. of l2a-hydrocortisone-3,20-diethylene ketal ()GJVI) in ml. of methanol and 1.5 ml. of 3 N sulfuric acid is refluxed for 40 minutes. After cooling, water is added, the mixture concentrated in vacuo to remove the bulk of the methanol and the resulting suspension extracted with ethyl acetate. The ethyl acetate extract is washed with dilute sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue is recrystallized from 95% alcohol and furnishes the pure 12a-chlorohydrocortisone (XLIX).

2% EXAMPLE 2s- M-pregnene-I 1,13,12fi-oxid0-1 7oc-21-di0l-3,20-dione (XL VIZ) A solution of 400 mg. of the 3-20-ethylene ketal of 12a-chlorohydrocortisone (XLVI) in 10 ml. of methanol and 2 ml. of 10% potassium carbonate in water is refluxed for one hour. The mixture is then neutralized with 3N aqueous sulfuric acid and when neutral treated with 1.5 ml. of sulfuric acid of the same strength. After 4 hours at room temperature, chloroform is added and the resulting chloroform extract is Washed with dilute sodium bicarbonate and water. Removal of the solvent leaves the 115,12fi-oxide (XLVII) as a crystalline residue, which is recrystallized from alcohol.

The 1l,12,8-oxide (XLVII) is acetylated with pyridineacetic anhydride to form A -pregnene-11fl,12fl-oxido-17a, 2l-diol-3,20-dione 2l-acetate (XLVIII).

EXAMPLE 26 IZa-bromohydrocortisone acetate (L) To a solution of mg. of M-pregnene-l1,3,12,6-oxidot,21-dl0l-3,20-dl0116 21-acetate (XLVIII) in 5 m1. of dioxane is added at 0 0.3 ml. of 48% HBr. The mixture is allowed to remain at 0 for one hour and is then diluted with chloroform and water. The chloroform extract is Washed with dilute sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is crystallized carefully from 95 alcohol.

EXAMPLE 27 12a-br0m0c0rtis0ne acetate 12a-bromohydrocortisone acetate (L) is oxidized with chromic acid-sulfuric acid in acetone as described in Example 2 to yield 12a-bromocortisone acetate.

The invention may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. 12a-ha1o-A -furostene-3/3,26-diol-1l-one 3,26-diacylate, wherein the acyl radical is the acyl radical of a hydrocarbon carboxylic acid of less than ten carbon atoms.

2. A process for preparing a diester of 12a-halo-A furostene-3fl,26-diol-1l-one, Which comprises treating the corresponding ester of 12a-halo-5oz-spirostane-3fl-ol-11- one with an acid anhydride and a Lewis acid, and recovering the resultant product.

3. 12a chloro-A -furostene-3,8,26-diol-1l-one 3,26- diacetate.

References Cited in the file of this patent UNITED STATES PATENTS 2,755,277 Wettstein et a1 July 17, 1956 2,870,143 Wall et a1 Jan. 20, 1959 FOREIGN PATENTS 531,444 Belgium Sept. 15, 1954 531,445 Belgium Sept. 15, 1954 OTHER REFERENCES Schmidlin et a1.: Helv. Chem. Acta, vol. 26, pages 1241- 51 (1953).

ES PATENT OFFICE F CORRECTION October 24 UNITED STA'IT CERTIFICATION O Patent No. 3 O05 $17 Josef Fried et a1.

ears in the tters Pa certified that error app above numbered pattent should read as It is hereby tion and that the said Le ent requiring correc corrected below.

'linesZ? to tead ofas in t 38 the formula should appear as he patent:

Column 5 CH Y' shown below ins same column 3,

below instea appear as shown Signed and sealed this 19th day of June I962,

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Commissioner of Patents Attesting Officer 

1. A 12A-HALO$20(22)-FUROSTENE-3B,26-DIOL-11-ONE 3,26-DIACYLATE, WHEREIN THE ACYL RADICAL IS THE ACYL RADICAL OF A HYDROCARBON CARBOXYLIC ACID OF LESS THAN TEN CARBON ATOMS. 